The long term objectives of this project are to determine the mechanisms by which H-2-linked immune response (Ir) genes regulate immune responses to T cell dependent antigens. Although the hypothesis that the Ia antigens are the Ir gene products is widely accepted, it does not explain how Ia antigens mediate the highly specific Ir gene functions. Our previous studies support the postulate that Ir gene control is the net result of the stimulation of various regulatory helper and suppressor T cell subsets. Thus, the specific aims of this proposal focus on the detailed characterization of differences in regulatory T cell subsets between responder and nonresponder mice. Development of antibody responses by inbred strains of mice to the synthetic polypeptides: L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) and L-glutamic acid50-L-tyrosine (GT) and a panel of proteins comprised of several insulin variants obtained from different species serve as model systems. Development of specific helper T cell clones and suppressor T cell hybridomas as sources of homogeneous regulatory T cells will be continued. The mechanisms by which suppressor T cells inhibit responses will be analyzed using soluble, antigen-specific suppressor factors and suppressor-inducer factors. The clinical importance of understanding precisely how Ir genes function is supported by evidence that Ir genes also regulate immune responses in humans. Several organ-specific autoimmune diseases are associated with certain haplotypes of the D/DR region of the HLA-complex suggesting that this locus is analogous to the murine I region. Thus, the role of Ir genes in development of experimental autoimmune diseases in mice will be investigated as a model system. Once the biology of suppressor T cells is well understood, it should be possible to produce suppressor factors to modulate indesirable immune responses specifically. Because it would not be feasible to design a new factor for every disease and every individual, we will determine whether specific factors can be targeted to neoantigenic determinants via an antigen bridge. If numerous responses can be suppressed with a single factor, the therapeutic potential of suppressor factors would be very promising. Ultimately these studies might provide the basis to prevent induction of anti-insulin antibodies in insulin-dependent diabetics and to reverse autoimmune diseases with specific suppressor T cell factors.